Modeling blood–brain barrier–glioblastoma interactions: implications for chemoresistance and therapeutic targeting

Glioblastoma (GBM) is the most aggressive and common primary brain tumor in adults and remains associated with a dismal prognosis despite standard-of-care treatment. A major contributor to therapeutic failure is the blood–brain barrier (BBB), which severely restricts the penetration of most therapeutic agents into the brain. In addition, the complex and dynamic interactions between GBM and its surrounding microenvironment, including the BBB, remain incompletely understood, largely due to limitations of existing experimental models. In this review, we outline the key anatomical and physiological features of the BBB and examine how its disruption in the peritumoral region and within GBM contributes to drug resistance. We then provide a critical comparison of current in vitro and in vivo models of the BBB–GBM interface, ranging from static culture systems to dynamic platforms and animal models, highlighting their respective strengths and limitations in recapitulating the tumor microenvironment and predicting drug delivery in human tumors. Particular attention is given to the extent to which these models capture vascular heterogeneity, cellular crosstalk, and barrier plasticity. Overall, this review integrates static and dynamic in vitro approaches with in vivo animal models to provide a comprehensive framework for understanding BBB–GBM interactions and their role in chemoresistance. Such models are essential for elucidating tumor-extrinsic mechanisms of drug resistance, identifying novel therapeutic targets, and improving the predictive value of preclinical studies. Notably, organoid-based BBB models emerge as highly promising dynamic platforms, as they more faithfully recapitulate the three-dimensional architecture, cellular heterogeneity, and microenvironmental interactions of GBM. Continued refinement of physiologically relevant models will be critical to accelerating the translation of effective therapeutic strategies into clinical practice.